The receptor activator of NF-κB ligand (RANKL) system is considered important for bone homeostasis and comprises three important factors. RANKL is a transmembrane ligand that binds to a specific receptor (receptor activator of NF-κB (RANK)) on a neighbor cell that subsequently activates NFKB and regulates cellular activation through regulation of cell cycle i.e proliferation, differentiation and apoptosis. OPG is an endogenous secreted protein that binds RANKL and inhibits its signalling.
RANK/RANKL triggers a network of TRAF-mediated kinase cascades that promote osteoclast differentiation. RANKL is expressed on osteoblast cells and its receptor, Rank, on pre-osteoclastic cells. RANKL expression is stimulated by a number of factors, such as IL-1 , IL-6, IL-11, IL-17, TNF-α, vitamin D, Ca2+, parathyroid, glucocorticoids, prostaglandin E2, and immunosuppressive drugs, and is down-regulated by TGF-α. The RANK/RANKL interaction induces differentiation and formation of multinucleated mature osteoclasts, causing bone resorption. The third protein agonist, osteoprotegerin (OPG), is also produced by osteoblasts and is known to exert an inhibitory effect on the pre-osteoclastic differentiation process. By binding to RANKL also known as osteoprotegerin binding protein (OPGbp), OPG inhibits the RANK/RANKL interaction and subsequent osteoclastogenesis. OPG is thus a very efficient anti-resorptive agent. It also serves as a decoy receptor for the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and increases cell survival by blocking the apoptotic effects of this ligand. The fact that the overexpression of OPG in mice results in severe osteopetrosis and that OPG-null mice are osteoporotic is testimony to the physiological importance of OPG. The lack of RANK or RANKL induces osteopetrosis in mice.
Thus, the RANK/RANKL system is vital for activation of the bone resorbing cells (osteoclasts). In bone, the bone synthesizing cells (osteblasts) express RANKL that signals to RANK on the immature osteoclasts. This induces proliferation and activation of the cells they start to proliferate and resorb bone. OPG is produced by somatic cells in the bone and this production is regulated by sex hormones, TGF-B and various other substances. Today a human made recombinant antibody against RANKL, denosumab is used to treat osteoporosis as it inhibits RANKL signalling and thus causes less bone resorption in humans. RANKL signalling has only two other known additional functions in healthy humans as it is involved in lactation and immune cells.
Recently, use of RANK/RANKL antagonists for treating neuromuscular disorders, genetic myopathies and/or non-genetic myopathies and/or for regulating skeletal and cardiac muscle disuse, diseases and aging has also been disclosed (WO 2013/067639 A1).
Decreased semen quality is a major factor of male infertility. Semen quality is a measure of the ability of the semen to accomplish fertilization. Evaluation of male fertility potential is today basically conducted through semen analysis. A semen analysis evaluates certain characteristics of a male's semen and the spermatozoa contained in the semen. The most common variables measured to evaluate sperm quality are: sperm count, motility and morphology. However, there is no treatment for men with no sperm in the ejaculate or a drug that can increase sperm number today.